Cobalamin conjugates useful as imaging agents and as antitumor agents

ABSTRACT

The invention provides cobalamin derivatives which are useful for medical treatment and diagnosis.

RELATED APPLICATION

The application claims priority to U.S. Provisional Application Ser. No.60/159,874, filed 15 Oct. 1999.

BACKGROUND OF THE INVENTION

Cancer is a general term frequently used to indicate any of the varioustypes of malignant neoplasms (i.e., abnormal tissue that grows bycellular proliferation more rapidly than normal), most of which invadesurrounding tissue, may metastasize to several sites, are likely torecur after attempted removal, and causes death unless adequatelytreated. Stedman's Medical Dictionary, 25th Edition Illustrated,Williams & Wilkins, 1990. Approximately 1.2 million Americans arediagnosed with cancer each year, 8,000 of which are children. Inaddition, 500,000 Americans die from cancer each year in the UnitedStates alone. Specifically, lung and prostate cancer are the top cancerkillers for men while lung and breast cancer are the top cancer killersfor women. It is estimated that cancer-related costs account for about10 percent of the total amount spent on disease treatment in the UnitedStates. CNN Cancer Facts,http://www.cnn.comi/HEALTH/9511/conquer_cancer/facts/index.html, page 2of 2, Jul. 18, 1999.

Although a variety of approaches to cancer therapy (e.g., surgicalresection, radiation therapy, and chemotherapy) have been available andcommonly used for many years, cancer remains one of the leading causesof death in the world. This is due in part to the therapies themselvescausing significant toxic side-effects as well as the re-emergence ofthe deadly disease.

The toxicity associated with conventional cancer chemotherapy is dueprimarily to a lack of specificity of the chemotherapeutic agent.Unfortunately, anti-cancer drugs by themselves typically do notdistinguish between malignant and normal cells. As a result, anti-cancerdrugs are absorbed by both cell types. Thus, conventionalchemotherapeutic agents not only destroy diseased cells, but alsodestroy normal, healthy cells. To overcome this limitation, therapeuticstrategies that increase the specificity, increase the efficacy, as wellas reduce the toxicity of anti-cancer drugs are being explored. One suchstrategy that is being aggressively pursued is drug targeting.

An objective of drug targeting is to deliver drugs to a specific site ofaction through a carrier system. Such targeting achieves at least twomajor aims of drug delivery. The first is to deliver the maximum dose oftherapeutic agent to diseased cells. The second is the avoidance ofuptake by normal, healthy cells. Thus, targeted drug delivery systemsresult in enhancing drug accumulation in tumors while decreasingexposure to susceptible healthy tissues. As such, the efficacy isincreased while the toxicity is decreased.

Two classes of compounds with a propensity for localizing in malignanttumors are the porphyrins and the related phthalocyanines. Thebiochemical basis by which these compounds achieve elevatedconcentration in malignant tumors is unknown, but this observation hasserved as the rationale for the use of hematoporphyrin derivatives inthe photodynamic therapy of cancer (Dougherty, T. J. et al., PorphyrinPhotosensitization, 3-13, New York: Plenum Publishing Corp. (1981)).

For several years after the isolation of vitamin B₁₂ as cyanocobalaminin 1948, it was assumed that cyanocobalamin and possiblyhydroxocobalamin, its photolytic breakdown product, occurred in man.Since then it has been recognized that cyanocobalamin is an artifact ofthe isolation of vitamin B₁₂ and that hydroxocobalamin and the twocoenzyme forms, methylcobalamin and adenosylcobalanin, are the naturallyoccurring forms of the vitamin.

The structure of these various forms is shown in FIG. 1, wherein X isCN, OH, CH₃ or adenosyl, respectively. Hereinafter, the term cobalaminwill be used to refer to all of the molecule except the X group. Thefundamental ring system without cobalt (Co) or side chains is calledcorrin and the octadehydrocorrin is called corrole. FIG. 1 is adaptedfrom The Merck Index, Merck & Co. (11th ed. 1989), wherein X is abovethe plane defined by the corrin ring and the nucleotide is below theplane of the ring. The corrin ring has attached seven amidoalkyl(H₂NC(O)Alk) substituents, at the 2, 3, 7, 8, 13, 18 and 23 positions,which can be designated a-g respectively. See D. L. Anton et al., J.Amer. Chem. Soc., 102, 2215 (1980). The 2, 3, 7, 8, and 13 positions areshown in FIG. 1 as positions a-e, respectively.

Cells undergoing rapid proliferation have been shown to have increaseduptake of thymidine and methionine. (See, for example, M. E. vanEijkeren et al., Acta Oncologica, 31, 539 (1992); K. Kobota et al., J.Nucl. Med., 32, 2118 (1991) and K. Higashi et al., J. Nucl. Med., 34,773 (1993)). Since methylcobalamin is directly involved with methioninesynthesis and indirectly involved in the synthesis of thymidylate andDNA, it is not surprising that methylcobalamin as well asCobalt-57-cyanocobalamin have also been shown to have increased uptakein rapidly dividing tissue (for example, see, B. A. Cooper et al.,Nature, 191, 393 (1961); H. Flodh, Acta Radiol. Suppl., 284, 55 (1968);L. Bloomquist et al., Experientia, 25, 294 (1969)). Additionally,up-regulation in the number of transcobalamin II receptors has beendemonstrated in several malignant cell lines during their acceleratedthymidine incorporation and DNA synthesis (see, J. Lindemans et al.,Exp. Cell. Res., 184, 449 (1989); T. Amagasaki et al., Blood, 26, 138(1990) and J. A. Begly et al., J. Cell Physiol., 156, 43 (1993).

PCT Application WO 98/08859 discloses bioconjugates (i.e., conjugatescontaining a bioactive agent and an organo-cobalt complex in which thebioactive agent is covalently bound directly or indirectly, via aspacer, to the cobalt atom). The organo-cobalt complex can be cobalaminand the bioactive agent can be a chemotherapeutic agent. However, onlyone bioactive agent (i.e., chemotherapeutic agent) is attached to theorgano-cobalt complex (i.e., cobalamin) and the attachment is to thecobalt atom (i.e., the 6-position of cobalamin). The bioactive agent isreleased from the bioconjugate by the cleavage of the weak covalent bondbetween the bioactive agent and the cobalt atom as a result of normaldisplacement by cellular nucleophiles or enzymatic action, or byapplication of an external signal (e.g., light, photoexcitation,ultrasound, or the presence of a magnetic filed).

Despite the above findings, there is currently a need forchemotherapeutic agents that have improved specificity (i.e., localizein tumor cells in high concentration compared to normal cells), orefficacy, and for chemotherapeutic agents which can selectively targetcancer cells.

SUMMARY OF THE INVENTION

Applicant has discovered cobalamin conjugates (i.e., conjugates ofVitamin B₁₂ and a chemotherapeutic agent) that are useful to treatand/or image tumors. The cobalamin conjugates have a low toxicity, ahigh activity against diseased cells, and a high specificity (i.e., theylocalize in tumor cells in a higher concentration than in normal cells).

The present invention provides a compound (i.e., cobalamin conjugate ofthe present invention) wherein a residue of a compound of formula I(FIG. 1) is linked directly or by a linker to a residue of one or morechemotherapeutic agents; wherein X is CN, OH, CH₃, or adenosyl; or apharmaceutically acceptable salt thereof.

The present invention also provides a compound (i.e., a cobalaminconjugate of the present invention) wherein a residue of a compound offormula I (FIG. 1) is linked directly or by a linker to a residue of achemotherapeutic agent through the 6-position and wherein a residue ofthe compound of formula I is linked directly or by a linker to a residueof one or more additional chemotherapeutic agents; or a pharmaceuticallyacceptable salt thereof.

The present invention also provides a compound (i.e., cobalaminconjugate of the present invention) of formula II

wherein

is a residue of the compound of formula I; X is CN, OH, CH₃, adenosyl,or LL-TT wherein LL is a linker or is absent and TT is a residue of achemotherapeutic agent; L is a linker or absent; and T is a residue of achemotherapeutic agent; or a pharmaceutically acceptable salt thereof.

The present invention also provides a compound (i.e., cobalaminconjugate of the present invention) of formula II

wherein

is a residue of the compound of formula I; X is LL-TT wherein LL is alinker or is absent and TT is a residue of a chemotherapeutic agent; Lis a linker or absent; and T is a residue of a chemotherapeutic agent;or a pharmaceutically acceptable salt thereof.

The present invention also provides a compound (i.e., cobalaminconjugate of the present invention) of formula III:

wherein X is CN, OH, CH₃, adenosyl, or ZZ-TT wherein ZZ is a linker oris absent and TT is a residue of a chemotherapeutic agent; Z is —N(R)—,—O—, —S—, or absent wherein R is H or (C₁-C₆)alkyl; and T is a residueof a chemotherapeutic agent; or a pharmaceutically acceptable saltthereof.

The present invention also provides a compound (i.e., cobalaminconjugate of the present invention) of formula III:

wherein X is LL-TT wherein LL is a linker or is absent and TT is aresidue of a chemotherapeutic agent; Z is —N(R)—, —O—, —S—, or absent,wherein R is H or (C₁-C₆)alkyl; and T is a residue of a chemotherapeuticagent; or a pharmaceutically acceptable salt thereof.

The present invention also provides a compound wherein a residue of acompound of formula I (FIG. 1) is linked directly or by a linker to aresidue of one or more chemotherapeutic agents; wherein X is CN, OH,CH₃, or adenosyl; wherein the compound of formula I is also linkeddirectly or by a linker to a detectable radionuclide; or apharmaceutically acceptable salt thereof.

The present invention also provides a pharmaceutical compositioncomprising a cobalamin conjugate of the present invention, or apharmaceutically acceptable salt thereof; and a pharmaceuticallyacceptable carrier.

The present invention also provides a method of treating a tumor in amammal in need of such treatment comprising administering to the mammalan effective amount of a cobalamin conjugate of the present invention,or a pharmaceutically acceptable salt thereof; and a pharmaceuticallyacceptable carrier.

The invention also provides a method for imaging a tumor in a mammal inneed of such imaging comprising administering to the mammal a detectableamount of a cobalamin conjugate of the present invention; and detectingthe presence of the compound.

The invention also provides a compound of the present invention for usein medical therapy or diagnosis.

The invention also provides the use of a compound of the presentinvention for the manufacture of a medicament for imaging a tumor in amammal (e.g., a human).

The invention also provides the use of a compound of the presentinvention for the manufacture of a medicament for treating a tumor in amammal (e.g., a human).

The invention also provides intermediates disclosed herein that areuseful in the preparation of the compounds of the present invention aswell as synthetic methods useful for preparing the compounds of theinvention.

The cobalamin conjugate of the present invention has severalcharacteristics which make it an attractive in vivo targeting agent.Vitamin B₁₂ is water soluble, has no known toxicity, and in excess isexcreted by glomerular filtration. In addition, the uptake of vitaminB₁₂ can potentially be manipulated by the administration of nitrousoxide and other pharmacological agents (D. Swanson et al.,Pharmaceuticals in Medical Imaging, MacMillan Pub. Co., NY (1990) atpages 621-628).

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 illustrates a compound of formula I, wherein X is CN, OH, CH₃,adenosyl or a residue of a chemotherapeutic agent. The compound offormula I can be cyanocobalamin (X is CN), hydroxocobalamin (X is OH),methylcobalamin (X is CH₃), or adenosylcobalamin (X is adenosyl). Inaddition, the compound of formula I can be a cobalamin conjugate (X is aresidue of a chemotherapeutic agent or X is a linker linked to a residueof a chemotherapeutic agent).

FIG. 2 illustrates a proposed synthesis of a compound wherein a residueof a compound of formula I is linked to linker, which is linked to aresidue of a chemotherapeutic agent.

DETAILED DESCRIPTION OF THE INVENTION

The following definitions are used, unless otherwise described: halo isfluoro, chloro, bromo, or iodo. Alkyl, alkoxy, alkenyl, alkynyl, etc.denote both straight and branched groups; but reference to an individualradical such as “propyl” embraces only the straight chain radical, abranched chain isomer such as “isopropyl” being specifically referredto. Aryl denotes a phenyl radical or an ortho-fused bicyclic carbocyclicradical having about nine to ten ring atoms in which at least one ringis aromatic.

Specific and preferred values listed below for radicals, substituents,and ranges, are for illustration only; they do not exclude other definedvalues or other values within defined ranges for the radicals andsubstituents.

It is appreciated that those skilled in the art will recognize thatcompounds of the present invention having a chiral center may exist inand be isolated in optically active and racemic forms. Some compoundsmay exhibit polymorphism. It is to be understood that the presentinvention encompasses any racemic, optically-active, polymorphic, orstereoisomeric form, or mixtures thereof, of a compound of theinvention, which possess the useful properties described herein, itbeing well known in the art how to prepare optically active forms (forexample, by resolution of the racemic form by recrystallizationtechniques, by synthesis from optically-active starting materials, bychiral synthesis, or by chromatographic separation using a chiralstationary phase) and how to determine antitumor activity using thestandard tests described herein, or using other similar tests which arewell known in the art.

Specifically, (C₁-C₆)alkyl can be methyl, ethyl, propyl, isopropyl,butyl, iso-butyl, sec-butyl, pentyl, 3-pentyl, or hexyl.

Specifically, (C₂-C₆)alkenyl can be vinyl, allyl, 1-propenyl,2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1,-pentenyl, 2-pentenyl,3-pentenyl, 4-pentenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, or5-hexenyl.

Specifically, (C₂-C₆)alkynyl can be ethynyl, 1-propynyl, 2-propynyl,1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl,4-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, or 5-hexynyl.

Specifically “aryl” can be phenyl, indenyl, or naphthyl.

Specifically (C₃-C₈)cycloalkyl can be cyclopropyl, cyclobutyl,cyclcopentyl, cyclohexyl, cycloheptyl or cyclooctyl.

As used herein, “adenosyl” is an adenosine radical in which anysynthetically feasible atom or group of atoms have been removed, therebyproviding an open valence. Synthetically feasible atoms which may beremoved include the hydrogen atom of the hydroxy group at the 5′position. Accordingly, adenosyl can conveniently be attached to the6-position (i.e., the position occupied by X in the compound of formulaI) of a compound of formula I via the 5′ position of adenosyl.

As used herein, a “residue of a compound of formula I” is a radical of acompound of formula I having an open valence. Any synthetically feasibleatom or atoms of the compound of formula I can be removed to provide theopen valence, provided the resulting compound is able to localize in ornear a tumor. Based on the linkage that is desired, one skilled in theart can select suitably functionalized starting materials that can bederived from a compound of formula I using procedures that are known inthe art. For example, suitable atoms that can be removed include the NH₂group of the a-carboxamide (illustrated in FIG. 1), the NH₂ group of theb-carboxamide (illustrated in FIG. 1), the NH₂ group of thed-carboxamide (illustrated in FIG. 1), the NH₂ group of the ecarboxamide (illustrated in FIG. 1), the hydrogen atom of the hydroxygroup at the 3′ position of the sugar, and the hydrogen atom of theCH₂OH group at the 5′ position of the sugar ring may be removed. Inaddition, X at the 6-position (illustrated in FIG. 1) can be removed toprovide an open valence to link a first chemotherapeutic agent.

As used herein, a “residue of a chemotherapeutic agent” is a radical ofa chemotherapeutic agent having an open valence. Any syntheticallyfeasible atom or atoms of the chemotherapeutic agent may be removed toprovide the open valence, provided the bioactivity of the agent isretained when administered as a conjugate of the invention. In addition,the residue of the chemotherapeutic agent does not comprise aradionuclide. Based on the linkage that is desired, one skilled in theart can select suitably functionalized starting materials that can bederived from a chemotherapeutic agent using procedures that are known inthe art.

As used herein, a “residue of doxorubicin or paclitaxel” is a radical ofdoxorubicin or a radical of paclitaxel having an open valence formed byremoving a substituent (i.e., atom or group of atoms) from doxorubicinor by removing a substituent (i.e., atom or group of atoms) frompaclitaxel. Any synthetically feasible atom or atoms of doxorubicin orpaclitaxel may be removed to provide the open valence, provided usefulbioactivity is retained when administered as a conjugate of theinvention. Based on the linkage that is desired, one skilled in the artcan select suitably functionalized starting materials that can bederived from doxorubicin or paclitaxel using procedures that are knownin the art.

As used herein, an “amino acid” is a natural amino acid residue (e.g.Ala, Arg, Asn, Asp, Cys, Glu, Gln, Gly, His, Hyl, Hyp, Ile, Leu, Lys,Met, Phe, Pro, Ser, Thr, Trp, Tyr, and Val) in D or L form, as well asunnatural amino acid (e.g. phosphoserine; phosphothreonine;phosphotyrosine; hydroxyproline; gamma-carboxyglutamate; hippuric acid;octahydroindole-2-carboxylic acid; statine;1,2,3,4,-tetrahydroisoquinoline-3-carboxylic acid; penicillamine;ornithine; citruline; α-methyl-alanine; para-benzoylphenylalanine;phenylglycine; propargylglycine; sarcosine; and tert-butylglycine)residue having one or more open valences. The term also comprisesnatural and unnatural amino acids bearing amino protecting groups (e.g.acetyl, acyl, trifluoroacetyl, or benzyloxycarbonyl), as well as naturaland unnatural amino acids protected at carboxy with protecting groups(e.g. as a (C₁-C₆)alkyl, phenyl or benzyl ester or amide). Othersuitable amino and carboxy protecting groups are known to those skilledin the art (See for example, T. W. Greene, Protecting Groups In OrganicSynthesis; Wiley: New York, 1981; D. Voet, Biochemistry, Wiley: NewYork, 1990; L. Stryer, Biochemistry, (3rd Ed.), W. H. Freeman and Co.:New York, 1975; J. March, Advanced Organic Chemistry Reactions,Mechanisms and Structure, (2nd Ed.), McGraw Hill: New York, 1977; F.Carey and R. Sundberg, Advanced Organic Chemistry Part B: Reactions andSynthesis, (2nd Ed.), Plenum: New York, 1977; and references citedtherein). According to the invention, the amino or carboxy protectinggroup can comprise a radionuclide (e.g., Fluorine-18, Iodine-123, orIodine-124).

As used herein, a “peptide” is a sequence of 2 to 25 amino acids (e.g.as defined herein) or peptidic residues. The sequence may be linear orcyclic. For example, a cyclic peptide can be prepared or may result fromthe formation of disulfide bridges between two cysteine residues in asequence. A peptide can be linked through the carboxy terminus, theamino terminus, or through any other convenient point of attachment,such as, for example, through the sulfur of a cysteine. Specifically, apeptide comprises 2 to about 20, 2 to about 15, or 2 to about 12 aminoacids. Peptide derivatives can be prepared as disclosed in U.S. Pat.Nos. 4,612,302; 4,853,371; and 4,684,620, or as described in theExamples herein. Peptide sequences specifically recited herein arewritten with the amino terminus on the left and the carboxy terminus onthe right.

Specifically, the peptide can be poly-L-lysine, poly-L-glutamic acid,poly-L-aspartic acid, poly-L-histidine, poly-L-ornithine, poly-L-serine,poly-L-threonine, poly-L-tyrosine, poly-L-lysine-L-phenylalanine orpoly-L-lysine-L-tyrosine.

Chemotherapeutic Agent

As used herein, a “chemotherapeutic agent” is a compound that hasbiological activity against one or more forms of cancer and can belinked to the residue of a compound of formula I without losing itsanticancer activity. Suitable chemotherapeutic agents includeantineoplasts. Representative antineoplasts include adjuncts, androgeninhibitors, antibiotic derivatives, antiestrogens, antimetabolites,cytotoxic agents, hormones, immunomodulators, nitrogen mustardderivatives and steroids. Physicians' Desk Reference, 50th Edition,1996.

Representative adjuncts include levamisole, gallium nitrate,granisetron, sargramostim strontium-89 chloride, filgrastim,pilocarpine, dexrazoxane, and ondansetron. Physicians' Desk Reference,50th Edition, 1996.

Representative androgen inhibitors include flutamide and leuprolideacetate. Physicians' Desk Reference, 50th Edition, 1996.

Representative antibiotic derivatives include doxorubicin, bleomycinsulfate, daunorubicin, dactinomycin, and idarubicin.

Representative antiestrogens include tamoxifen citrate and analogsthereof. Physicians' Desk Reference, 50th Edition, 1996. Additionalantiestrogens include nonsteroidal antiestrogens such as toremifene,droloxifene and roloxifene. Magarian et al., Current MedicinalChemistry, 1994, Vol. 1, No. 1.

Representative antimetabolites include fluorouracil, fludarabinephosphate, floxuridine, interferon alfa-2b recombinant, methotrexatesodium, plicamycin, mercaptopurine, and thioguanine. Physicians' DeskReference, 50th Edition, 1996.

Representative cytotoxic agents include doxorubicin, carmustine [BCNU],lomustine [CCNU], cytarabine USP, cyclophosphamide, estramucinephosphate sodium, altretamine, hydroxyurea, ifosfamide, procarbazine,mitomycin, busulfan, cyclophosphamide, mitoxantrone, carboplati,cisplati, cisplatin, interferon alfa-2a recombinant, paclitaxel,teniposide, and streptozoci. Physicians' Desk Reference, 50th Edition,1996.

Representative hormones include medroxyprogesterone acetate, estradiol,megestrol acetate, octreotide acetate, diethylstilbestrol diphosphate,testolactone, and goserelin acetate. Physicians' Desk Reference, 50thEdition, 1996.

Representative immunodilators include aldesleukin. Physicians' DeskReference, 50th Edition, 1996.

Representative nitrogen mustard derivatives include melphalan,chlorambucil, mechlorethamine, and thiotepa. Physicians' Desk Reference,50th Edition, 1996.

Representative steroids include betamethasone sodium phosphate andbetamethasone acetate. Physicians' Desk Reference, 50th Edition, 1996.

Specifically, the chemotherapeutic agent can be an antineoplastic agent.

Specifically, the antineoplastic agent can be a cytotoxic agent.

Specifically, the cytotoxic agent can be paclitaxel or doxorubicin.

Additional suitable chemotherapeutic agents include alkylating agents,antimitotic agents, plant alkaloids, biologicals, topoisomerase Iinhibitors, topoisomerase II inhibitors, and synthetics. AntiCancerAgents by Mechanism,http://www.dtp.nci.nih.gov/docs/cancer/searches/standard_mechanism_list.html,Apr. 12, 1999; Approved Anti-Cancer Agents,http://www.ctep.info.nih.gov/handbook/HandBookText/fda_agen.htm, pages1-7, Jun. 18, 1999; MCMP 611 Chemotherapeutic Drugs to Know,http//www.vet.purdue.edu/depts/bms/courses/mcmp611/chrx/drg2no61.html,Jun. 24, 1999; and Chemotherapy,http://www.vetmed.lsu.edu/oncology/Chemotherapy.htm, Apr. 12, 1999.

Representative alkylating agents include asaley, AZQ, BCNU, busulfan,bisulphan, carboxyphthalatoplatinum, CBDCA, CCNU, CHIP, chlorambucil,chlorozotocin, cis-platinum, clomesone, cyanomorpholinodoxo-rubicin,cyclodisone, cyclophosphamide, dianhydrogalactitol, fluorodopan,hepsulfam, hycanthone, iphosphamide, melphalan, methyl CCNU, mitomycinC, mitozolamide, nitrogen mustard, PCNU, piperazine, piperazinedione,pipobroman, porfiromycin, spirohydantoin mustard, streptozotocin,teroxirone, tetraplatin, thiotepa, triethylenemelamine, uracil nitrogenmustard, and Yoshi-864. AntiCancer Agents by Mechanism,http://dtp.nci.nih.gov/docs/cancer/searches/standard_mechanism_list.html,Apr. 12, 1999.

Representative antimitotic agents include allocolchicine, HalichondrinB, colchicine, colchicine derivatives, dolastatin 10, maytansine,rhizoxin, paclitaxel derivatives, paclitaxel, thiocolchicine, tritylcysteine, vinblastine sulfate, and vincristine sulfate. AntiCancerAgents by Mechanism,http://dtp.nci.nih.gov/docs/cancer/searches/standard_mechanism_list.html,Apr. 12, 1999.

Representative plant alkaloids include actinomycin D, bleomycin,L-asparaginase, idarubicin, vinblastine sulfate, vincristine sulfate,mitramycin, mitomycin, daunorubicin, VP-16-213, VM-26, navelbine andtaxotere. Approved Anti-Cancer Agents,http://ctep.info.nih.gov/handbook/HandBookText/fda agent.htm, Jun. 18,1999.

Representative biologicals include alpha interferon, BCG, G-CSF, GM-CSF,and interleukin-2. Approved Anti-Cancer Agents,http://ctep.info.nih.gov/handbook/HandBookText/fda_agent.htm, Jun. 18,1999.

Representative topoisomerase I inhibitors include camptothecin,camptothecin derivatives, and morpholinodoxorubicin. AntiCancer Agentsby Mechanism,http://dtp.nci.nih.gov/docs/cancer/searches/standard_mechanism_list.html,Apr. 12, 1999.

Representative topoisomerase II inhibitors include mitoxantron,amonafide, m-AMSA, anthrapyrazole derivatives, pyrazoloacridine,bisantrene HCl, daunorubicin, deoxydoxorubicin, menogaril, N,N-dibenzyldaunomycin, oxanthrazole, rubidazone, VM-26 and VP-16. AntiCancer Agentsby Mechanism,http://dtp.nci.nih.gov/docs/cancer/searches/standard_mechanism_list.html,Apr. 12, 1999.

Representative synthetics include hydroxyurea, procarbazine, o,p′-DDD,dacarbazine, CCNU, BCNU, cis-diamminedichloroplatimun, mitoxantrone,CBDCA, levamisole, hexamethylmelamine, all-trans retinoic acid, gliadeland porfimer sodium. Approved Anti-Cancer Agents,http://ctep.info.nih.gov/handbook/HandBookText/fda agen.htm, Jun. 18,1999.

Compound of Formula I/Chemotherapeutic Agent Linkage

The residue of a chemotherapeutic agent can be directly linked to theresidue of a compound of formula I through an amide (e.g., —N(R)C(═O)—or —C(═O)N(R)—), ester (e.g., —OC(═O)— or —C(═O)O—), ether (e.g., —O—),amino (e.g., —N(R)—), ketone (e.g., —C(═O)—), thioether (e.g., —S—),sulfinyl (e.g., —S(O)—), sulfonyl (e.g., —S(O)₂—), or a direct (e.g.,C—C bond) linkage, wherein each R is independently H or (C₁-C₆)alkyl.Such a linkage can be formed from suitably functionalized startingmaterials using synthetic procedures that are known in the art. Based onthe linkage that is desired, one skilled in the art can select suitablyfunctional starting materials that can be derived from a residue of acompound of formula I and from a given residue of a chemotherapeuticagent using procedures that are known in the art.

The residue of the chemotherapeutic agent can be directly linked to anysynthetically feasible position on the residue of a compound of formulaI, provided if a residue of a chemotherapeutic agent is attached to aresidue of a compound of formula I at the 6-position, the residue of acompound of formula I is attached to a residue of anotherchemotherapeutic agent or to a detectable radionuclide. Suitable pointsof attachment include, for example, the b-carboxamide, thed-carboxamide, and the e-carboxamide (illustrated in FIG. 1), as well asthe 6-position (the position occupied by X in FIG. 1), and the5′-hydroxy and the 3′-hydroxy groups on the 5-membered sugar ring,although other points of attachment are possible. U.S. Pat. No.5,739,313 discloses compounds (e.g.,cyanocobalamin-b-(4-aminobutyl)amide,methylcobalamin-b-(4-aminobutyl)amide, andadenosylcobalamin-b-(4-aminobutyl)amide) that are useful intermediatesfor the preparation of compounds of the present invention.

Compounds wherein the residue of a chemotherapeutic agent is directlylinked to the 6-position of a compound of formula I can be prepared byreducing a corresponding Co (II) compound of formula I to form anucleophilic Co (I) compound and treating this Co (I) compound with aresidue of a chemotherapeutic agent (or a derivative thereof) comprisinga suitable leaving group, such as a halide (e.g., a chloride).

The invention also provides compounds having more than onechemotherapeutic agent directly attached to a compound of formula I. Forexample, the residue of a chemotherapeutic agent can be directly linkedto a residue of the b-carboxamide of the compound of formula I and aresidue of another chemotherapeutic agent can be directly linked to aresidue of the d-carboxamide of the compound of formula I. In addition,the residue of a chemotherapeutic agent can be directly linked to the6-position of the compound of formula I and a residue of anotherchemotherapeutic agent can be directly linked to a residue of the b-, d-or e-carboxamide of the compound of formula I.

In addition to being directly linked to the residue of a compound offormula I, the residue of a chemotherapeutic agent can also be linked tothe residue of a compound of formula I by a suitable linker. Thestructure of the linker is not crucial, provided it yields a compound ofthe invention which has an effective therapeutic index against thetarget cells, and which will localize in or near tumor molecules, whichproperties can be determined by those skilled in the art with assaysthat are known in the art.

Suitable linkers include linkers that separate the residue of a compoundof formula I and the chemotherapeutic agent by about 5 angstroms toabout 200 angstroms, inclusive, in length. Other suitable linkersinclude linkers that separate the residue of a compound of formula I andthe chemotherapeutic agent by about 5 angstroms to about 100 angstroms,as well as linkers that separate the residue of a compound of formula Iand the chemotherapeutic agent by about 5 angstroms to about 50angstroms, or by about 5 angstroms to about 25 angstroms. Suitablelinkers are disclosed, for example, in U.S. Pat. No. 5,735,313.

Specifically, the linker can be a divalent radical of the formula W-A-Qwherein A is (C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl,(C₃-C₈)cyclo-alkyl, or (C₆-C₁₀)aryl, wherein W and Q are eachindependently —N(R)C(═O)—, —C(═O)N(R)—, —OC(═O)—, —C(═O)O—, —O—, —S—,—S(O)—, —S(O)₂—, —N(R)—, —C(═O)—, or a direct bond; wherein each R isindependently H or (C₁-C₆)alkyl.

Specifically, the linker can be a divalent radical, i.e., 1,-divalentradicals formed from a peptide or an amino acid. The peptide cancomprise 2 to about 20 amino acids, 2 to about 15 amino acids, or 2 toabout 12 amino acids. The peptide or amino acid can optionally beprotected, as described herein.

Specifically, the peptide can be poly-L-lysine (i.e.,[—NHCH—[(CH₂)₄NH₂]CO-]_(m)-Q, wherein Q is H, (C₁-C₁₄)alkyl, or asuitable carboxy protecting group; and wherein m is about 2 to about20). Specifically, poly-L-lysine contains about 5 to about 15 residues(i.e., m is between about 5 and about 15). More specifically,poly-L-lysine contains about 8 to about 11 residues (i.e., m is betweenabout 8 and about 11).

Specifically, the peptide can be poly-L-glutamic acid, poly-L-asparticacid, poly-L-histidine, poly-L-ornithine, poly-L-serine,poly-L-threonine, poly-L-tyrosine, poly-L-lysine-L-phenylalanine orpoly-L-lysine-L-tyrosine.

Specifically, the linker can be prepared from 1,6-diaminohexaneH₂N(CH₂)₆NH₂, 1,5-diaminopentane H₂N(CH₂)₅NH₂, 1,4-diaminobutaneH₂N(CH₂)₄NH₂, or 1,3-diaminopropane H₂N(CH₂)₃NH₂.

Compound of Formula I/Linker/Chemotherapeutic Agent Linkage

The linker can be linked to (1) the residue of a chemotherapeutic agentand/or (2) the residue of a compound of formula I through an amide(e.g., —N(R)C(═O)— or —C(═O)N(R)—), ester (e.g., —OC(═O)— or —C(═O)O—),ether (e.g., —O—), amino (e.g., —N(R)—), ketone (e.g., —C(═O)—),thioether (e.g., —S—), sulfinyl (e.g., —S(O)—), sulfonyl (e.g.,—S(O)₂—), or a direct (e.g., C—C bond) linkage, wherein each R isindependently H or (C₁-C₆)alkyl. Such a linkage can be formed fromsuitably functionalized starting materials using synthetic proceduresthat are known in the art. Based on the linkage that is desired, oneskilled in the art can select suitably functional starting materialsthat can be derived from a residue of a compound of formula I and from agiven residue of a chemo-therapeutic agent using procedures that areknown in the art.

The linker can be linked to any synthetically feasible position on theresidue of a compound of formula I, provided if a linker is attached toa residue of a compound of formula I at the 6-position, at least oneresidue of a chemotherapeutic agent is linked directly or by a linker toa residue of the compound of formula I at a position other than the6-position (i.e., the position occupied by X in the compound of formulaI). Suitable points of attachment include, for example, a residue of theb-carboxamide, a residue of the d-carboxamide, and a residue of thee-carboxamide, the 6-position, as well as a residue of the 5′-hydroxygroup and a residue of the 3′-hydroxy group on the 5-membered sugarring, although other points of attachment are possible.

Compounds wherein the linker is linked to the 6-position of a compoundof formula I can be prepared by preparing a nucleophilic Co (I) speciesas described herein above, and reacting it with a linker comprising asuitable leaving group, such as a halide (e.g. a chloride).

The invention also provides compounds having more than onechemotherapeutic agent attached to a compound of formula I, each througha linker. For example, the residue of a chemotherapeutic agent canconveniently be linked, through a linker, to a residue of theb-carboxamide of the compound of formula I and a residue of anotherchemotherapeutic agent can conveniently be linked, through a linker, toa residue of the d- or e-carboxamide of the compound of formula I. Inaddition, the residue of a chemotherapeutic agent can conveniently belinked, through a linker, to the 6-position of the compound of formula Iand a residue of another chemotherapeutic agent can conveniently belinked, through a linker, to a residue of the b-, d- or e-carboxamide ofthe compound of formula I.

The invention also provides compounds having more than onechemotherapeutic agent attached to a compound of formula I, eitherdirectly or through a linker. For example, the residue of achemotherapeutic agent can conveniently be linked, either directly orthrough a linker, to a residue of the b-carboxamide of the compound offormula I and a residue of another chemotherapeutic agent canconveniently be linked, either directly or through a linker, to aresidue of the d- or e-carboxamide of the compound of formula I. Inaddition, the residue of a chemotherapeutic agent can conveniently belinked, either directly or through a linker, to the 6-position of thecompound of formula I and a residue of another chemotherapeutic agentcan conveniently be linked, either directly or through a linker, to aresidue of the b-, d- or e-carboxamide of the compound of formula I.

Applicant has also discovered that it is possible to prepare a compoundthat is useful for both imaging and for treating tumors by incorporatingone or more chemotherapeutic agents into a compound that also comprisesone or more detectable radionuclides. Accordingly, the inventionprovides a residue of a compound of formula I which is linked to one ormore residues of a chemotherapeutic agent; and which is also linked,directly or by a linker, to one or more detectable chelating groupsincluding one or more detectable radionuclides.

Compound of Formula I/Linker/Detectable Chelating Group Linkage

The detectable chelating group can be linked to a residue of thecompound of formula I by a linker. Suitable linkers are describedherein. In addition, suitable points of attachment of the compound offormula I for the linker including the detectable chelating group aredescribed herein.

A detectable chelating group including a radionuclide can be linked, viaa linker, to a residue of a compound of the formula I. The linker can belinked to any synthetically feasible position on the residue of aresidue of a compound of formula I; provided the compound localizes inor near tumors. Suitable points of attachment include, for example, aresidue of the b-carboxamide, a residue of the d-carboxamide, and aresidue of the e-carboxamide, the 6-position, as well as a residue ofthe 5′-hydroxy group and a residue of the 3′-hydroxy group on the5-membered sugar ring, although other points of attachment are possible.

The invention also provides compounds having more than one detectablechelating group attached to a compound of formula I, each through alinker. For example, the detectable chelating group can conveniently belinked, through a linker, to a residue of the b-carboxamide of thecompound of formula I and another detectable chelating group canconveniently be linked, through a linker, to a residue of the d- ore-carboxamide of the compound of formula I. In addition, the detectablechelating group can conveniently be linked, through a linker, to the6-position of the compound of formula I and another detectable chelatinggroup can conveniently be linked, through a linker, to a residue of theb-, d- or e-carboxamide of the compound of formula I.

The invention also provides compounds having more than one detectableradionuclide attached to a residue of the compound of formula I, eitherdirectly or through a linker.

Detectable Chelating Group

A “detectable chelating group” is a chelating group comprising ametallic radionuclide (e.g., a metallic radioisotope) capable of beingdetected in a diagnostic procedure in vivo or in vitro. Any suitablechelating group can be employed. Suitable chelating groups include thosedisclosed in U.S. Pat. No. 5,739,313. Specifically, the chelating groupcan be NTA, HEDTA, DCTA, RP414, MDP, DOTATOC, CDTA, HYNIC, EDTA, DTPA,TETA, DOTA, DOTMP, DCTA, 15N4, 9N3, 12N3, or MAG3 (or another suitablepolyamino acid chelator), which are described herein below, or aphosphonate chelator (e.g. EDMT). More specifically, the chelating groupcan be. DTPA.

DTPA is diethylenetriaminepentaacetic acid; TETA is1,4,8,11-tetraazacyclotetradecane-N,N′,N″,N′″-tetraacetic acid; DOTA is1,4,7,10-tetraazacyclododecane-N,N′,N″,N′″-tetraacetic acid; 15N4 is1,4,8,12-tetraazacyclopentadecane-N,N′,N″,N′″-tetraacetic acid; 9N3 is1,4,7-triazacyclononane-N,N′,N″-triacetic acid; 12N3 is1,5,9-triazacyclododecane-N,N′,N″-triacetic acid; MAG3 is(N-[N-[N-[(benzoylthio)acetyl]glycyl]glycyl]-glycine); and DCTA is acyclohexane-based metal chelator of the formula

wherein R³ may by (C₁-C₄)alkyl or CH₂CO₂—, which may be attached throughpositions 4 or 5, or through the group R³ and which carries from 1 to 4detectable metal or nonmetal cations (M), monovalent cations, or thealkaline earth metals. Thus, with metals of oxidation state+1, eachindividual cyclohexane-based molecule may carry up to 4 metal cations(where both R³ groups are CH₂COOM). As is more likely, with higheroxidation states, the number of metals will decrease to 2 or even 1 percyclohexane skeleton. This formula is not intended to limit the moleculeto any specific stereochemistry.

NTA, HEDTA, and DCTA are disclosed in Poster Sessions, Proceedings ofthe 46th Annual Meeting, J. Nuc. Med., p. 316, No. 1386. RP414 isdisclosed in Scientific Papers, Proceedings of the 46th Annual Meeting,J. Nuc. Med., p. 123, No. 499. MDP is disclosed in Scientific Papers,Proceedings of the 46th Annual Meeting, J. Nuc. Med., p. 102, No. 413.DOTATOC is disclosed in Scientific Papers, Proceedings of the 46thAnnual Meeting, J. Nuc. Med., p. 102, No. 414 and Scientific Papers,Proceedings of the 46th Annual Meeting, J. Nuc. Med., p. 103, No. 415.CDTA is disclosed in Poster Sessions, Proceedings of the 46th AnnualMeeting, J. Nuc. Med., p. 318, No. 1396. HYNIC is disclosed in PosterSessions, Proceedings of the 46th Annual Meeting, J. Nuc. Med., p. 319,No. 1398.

Bifunctional chelators (i.e., chelating groups) based on macrocyclicligands in which conjugation is via an activated arm attached to thecarbon backbone of the ligand can also be employed as a chelating group,as described by M. Moi et al., J. Amer. Chem., Soc., 49, 2639 (1989)(2-p-nitro-benzyl-1,4,7,10-tetraazacyclododecane-N,N′,N″,N′″-tetraaceticacid); S. V. Deshpande et al., J. Nucl. Med., 31, 473 (1990); G. Kuseret al., Bioconj. Chem., 1, 345 (1990); C. J. Broan et al., J. C. S.Chem. Comm., 23, 1739 (1990); and C. J. Anderson et al., J. Nucl. Med.36, 850 (1995)(6-bromoacetamido-benzyl-1,4,8,11-tetraazacyclotetadecane-N,N′,N″,N′″-tetraaceticacid (BAT)).

In addition, the diagnostic chelator or diagnostic chelating groups canbe any of the chelating groups disclosed in Scientific Papers,Proceedings of the 46th Annual Meeting, J. Nuc. Med., Wednesday, Jun. 9,1999, p. 124, No. 500.

Specifically, the chelating group can be any one of the carbonylcomplexes disclosed in Waibel et al., Nature Biotechnology, 897-901,Vol. 17, September 1999; or Sattelberger et al., Nature Biotechnology,849-850, Vol. 17, September 1999.

Specifically, the detectable chelating group can be any of the carbonylcomplexes disclosed in Waibel et al., Nature Biotechnology, 897-901,Vol. 17, September 1999; or Sattelberger et al., Nature Biotechnology,849-850, Vol. 17, September 1999, further comprising a metallicradionuclide. More specifically, the detectable chelating group can beany of the carbonyl complexes disclosed in Waibel et al., NatureBiotechnology, 897-901, Vol. 17, September 1999; or Sattelberger et al.,Nature Biotechnology, 849-850, Vol. 17, September 1999, furthercomprising Technetium-99m.

Specifically, the detectable chelating group can be any of the carbonylcomplexes disclosed in Waibel et al., Nature Biotechnology, 897-901,Vol. 17, September 1999; or Sattelberger et al., Nature Biotechnology,849-850, Vol. 17, September 1999, further comprising a metallicradionuclide. More specifically, the detectable chelating group can beany of the carbonyl complexes disclosed in Waibel et al., NatureBiotechnology, 897-901, Vol. 17, September 1999; or Sattelberger et al.,Nature Biotechnology, 849-850, Vol. 17, September 1999, furthercomprising Rhenium-186 or Rhenium-188.

As used herein, a “detectable radionuclide” is any suitable radionuclide(i.e., radioisotope) capable of being detected in a diagnostic procedurein vivo or in vitro. Suitable detectable radionuclides include metallicradionuclides (i.e., metallic radioisotopes) and non-metallicradionuclides (i.e., non-metallic radioisotopes).

Metallic Radionuclides

Suitable metallic radionuclides (i.e., metallic radioisotopes ormetallic paramagnetic ions) include Antimony-124, Antimony-125,Arsenic-74, Barium-103, Barium-140, Beryllium-7, Bismuth-206,Bismuth-207, Cadmium-109, Cadmium-15m, Calcium-45, Cerium-139,Cerium-141, Cerium-144, Cesium-137, Chromium-51, Cobalt-55, Cobalt-56,Cobalt-57, Cobalt-58, Cobalt-60, Cobalt-64, Copper-67, Erbium-169,Europium-152, Gallium-64, Gallium-68, Gadolinium-153, Gadolinium-157Gold-195, Gold-199, Hafnium-175, Hafiium-175-181, Holmium-166,Indium-110, Indium-111, Iridium-192, Iron-55, Iron-59, Krypton-85,Lead-210, Manganese-54, Mercury-197, Mercury-203, Molybdenum-99,Neodymium-147, Neptunium-237, Nickel-63, Niobium-95, Osmium-185+191,Palladium-103, Platinum-195m, Praseodymium-143, Promethium-147,Protactinium-233, Radium-226, Rhenium-186, Rhenium-188, Rubidium-86,Ruthenium-103, Ruthenium-106, Scandium-44, Scandium-46, Selenium-75,Silver-110m, Silver-11, Sodium-22, Strontium-85, Strontium-89,Strontium-90, Sulfur-35, Tantalum-182, Technetium-99m, Tellurium-125,Tellurium-132, Thallium-204, Thorium-228, Thorium-232, Thallium-170,Tin-113, Tin-114, Tin-117m, Titanium-44, Tungsten-185, Vanadium-48,Vanadium-49, Ytterbium-169, Yttrium-86, Yttrium-88, Yttrium-90,Yttrium-91, Zinc-65, and Zirconium-95.

Non-Metallic Radionuclides

The compounds of the invention can also comprise one or more (e.g., 1,2, 3, or 4) non-metallic radionuclide which can be directly linked to aresidue of the compound of formula I at any synthetically feasible site,or can be linked to a residue of the compound of formula I, by a linker,at any synthetically feasible site. Suitable linkers are describedherein. In addition, suitable points of attachment of a the compound offormula I for the non-metallic radionuclide, either directly or by alinker, are also described herein. The invention also provides compoundshaving more than one non-metallic radionuclide attached to a compound offormula I, either directly, or by a linker.

Specifically, the non-metallic radionuclide can be a non-metallicparamagnetic atom (e.g., Fluorine-19); or a non-metallic positronemitting radionuclide (e.g., Carbon-11, Fluorine-18, Iodine-123, orBromine-76). Fluorine-18 is a suitable non-metallic radionuclide for usethe compounds of the present invention in part because there istypically little or no background noise associated with the diagnosticuse of fluorine in the body of a mammal (e.g., human). Preferably, thedetectable radionuclide is a non-metallic radionuclide, e.g., Carbon-11,Fluorine-18, Bromine-76, Iodine-123, Iodine-124.

The compounds disclosed herein can be prepared using procedures similarto those described in U.S. Pat. No. 5,739,313, or using proceduressimilar to those described herein. The residue of a molecules comprisingB-10 can be linked to the residue of a compound of formula I asdescribed herein. Additional compounds, intermediates, and syntheticpreparations thereof are disclosed, for example, in Hogenkamp, H. etal., Synthesis and Characterization of nido-Carborane-CobalaminConjugates, Nucl. Med. & Biol., 2000, 27, 89-92; Collins, D., et al.,Tumor Imaging Via Indium 111-Labeled DTPA-Adenosylcobalamin, Mayo ClinicProc., 1999, 74:687-691; U.S. Application Ser. No. 60/129,733 filed 16Apr. 1999; U.S. Application Ser. No. 60/159,874 filed 15 Oct. 1999; U.S.Application Ser. No. 60/159,753 filed 15 Oct. 1999; U.S. ApplicationSer. No. 60/159,873 filed 15 Oct. 1999; and references cited therein.

A specific compound of the present invention is compound wherein aresidue of the compound of formula I is linked directly or by a linkerto a residue of a chemotherapeutic agent; wherein X is CN; or apharmaceutically acceptable salt thereof.

Another specific compound of the present invention is compound wherein aresidue of the compound of formula I is linked directly or by a linkerto a residue of a chemotherapeutic agent; wherein the compound offormula I is linked directly or by a linker to a detectableradionuclide; wherein X is CN; or a pharmaceutically acceptable saltthereof.

Another specific compound of the present invention is a compound whereina residue of a chemotherapeutic agent is linked directly or by a linkerto a residue of the b-, d-, or e-carboxamide of a compound of formula I;or a pharmaceutically acceptable salt thereof.

Another specific compound of the present invention is a compound whereina residue of a chemotherapeutic agent is linked directly or by a linkerto a residue of the b-, d-, or e-carboxamide of a compound of formula I;wherein a detectable radionuclide is linked directly or by a linker to aresidue of the b-, d-, or e-carboxamide of a compound of formula I; or apharmaceutically acceptable salt thereof.

Another specific compound of the present invention is a compound whereina residue of a compound of formula I, wherein X is CN is linked directlyor by a linker to a residue of an antineoplastic agent; or apharmaceutically acceptable salt thereof.

Another specific compound of the present invention is a compound whereina residue of a compound of formula I, wherein X is CN is linked directlyor by a linker to a residue of an antineoplastic agent; wherein aresidue of a compound of formula I is linked directly or by a linker toa detectable radionuclide; or a pharmaceutically acceptable saltthereof.

Another specific compound of the present invention is a compound whereina residue of a compound of formula I, wherein X is CN is linked directlyor by a linker to a residue of paclitaxel or doxorubicin; or apharmaceutically acceptable salt thereof.

Another specific compound of the present invention is a compound whereina residue of a compound of formula I, wherein X is CN is linked directlyor by a linker to a residue of paclitaxel or doxorubicin; wherein aresidue of a compound of formula I is linked directly or by a linker toa detectable radionuclide; or a pharmaceutically acceptable saltthereof.

Another specific compound of the present invention is a compound whereina residue of the compound of formula I is linked directly or by a linkerto a residue of paclitaxel or doxorubicin at the b-, d-, ore-carboxamide; or a pharmaceutically acceptable salt thereof.

Another specific compound of the present invention is a compound whereina residue of the compound of formula I is linked directly or by a linkerto a residue of paclitaxel or doxorubicin at the b-, d-, ore-carboxamide; wherein a residue of a compound of formula I is linkeddirectly or by a linker to a detectable radionuclide; or apharmaceutically acceptable salt thereof.

In cases where compounds are sufficiently basic or acidic to form stablenontoxic acid or base salts, administration of the compounds as saltsmay be appropriate. Examples of pharmaceutically acceptable salts areorganic acid addition salts formed with acids which form a physiologicalacceptable anion, for example, tosylate, methanesulfonate, acetate,citrate, malonate, tartarate, succinate, benzoate, ascorbate,α-ketoglutarate, and α-glycerophosphate. Suitable inorganic salts mayalso be formed, including, sulfate, nitrate, bicarbonate, and carbonatesalts.

Pharmaceutically acceptable salts may be obtained using standardprocedures well known in the art, for example by reacting a sufficientlybasic compound such as an amine with a suitable acid affording aphysiologically acceptable anion. Alkali metal (for example, sodium,potassium or lithium) or alkaline earth metal (for example calcium)salts of carboxylic acids can also be made.

The present invention provides a method of treating a tumor in a mammal.The tumor can be located in any part of the mammal. Specifically, thetumor can be located in the breast, lung, thyroid, lymph node,genitourinary system (e.g., kidney, ureter, bladder, ovary, teste, orprostate), musculoskeletal system (e.g., bones, skeletal muscle, or bonemarrow), gastrointestinal tract (e.g., stomach, esophagus, small bowel,colon, rectum, pancreas, liver, or smooth muscle), central or peripheralnervous system (e.g., brain, spinal cord, or nerves), head and necktumors (e.g., ears, eyes, nasopharynx, oropharynx, or salivary glands),or the heart.

The compound of the present invention (cobalamin conjugates) can beformulated as pharmaceutical compositions and administered to amammalian host, such as a human patient in a variety of forms adapted tothe chosen route of administration, i.e., orally or parenterally, byintravenous, intramuscular, or subcutaneous routes.

Thus, the cobalamin conjugates may be systemically administered, e.g.,orally, in combination with a pharmaceutically acceptable vehicle suchas an inert diluent or an assimilable edible carrier. They may beenclosed in hard or soft shell gelatin capsules, may be compressed intotablets, or may be incorporated directly with the food of the patient'sdiet. For oral therapeutic administration, the substance may be combinedwith one or more excipients and used in the form of ingestible tablets,buccal tablets, troches, capsules, elixirs, suspensions, syrups, wafers,and the like. Such compositions and preparations should contain at least0.1% of the substance. The percentage of the compositions andpreparations may, of course, be varied and may conveniently be betweenabout 2 to about 60% of the weight of a given unit dosage form. Theamount of substance in such therapeutically useful compositions is suchthat an effective dosage level will be obtained.

The tablets, troches, pills, capsules, and the like may also contain thefollowing: binders such as gum tragacanth, acacia, corn starch orgelatin; excipients such as dicalcium phosphate; a disintegrating agentsuch as corn starch, potato starch, alginic acid and the like; alubricant such as magnesium stearate; and a sweetening agent such assucrose, fructose, lactose or aspartame or a flavoring agent such aspeppermint, oil of wintergreen, or cherry flavoring may be added. Whenthe unit dosage form is a capsule, it may contain, in addition tomaterials of the above type, a liquid carrier, such as a vegetable oilor a polyethylene glycol. Various other materials may be present ascoatings or to otherwise modify the physical form of the solid unitdosage form. For instance, tablets, pills, or capsules may be coatedwith gelatin, wax, shellac or sugar and the like. A syrup or elixir maycontain the active compound, sucrose or fructose as a sweetening agent,methyl and propylparabens as preservatives, a dye and flavoring such ascherry or orange flavor. Of course, any material used in preparing anyunit dosage form should be pharmaceutically acceptable and substantiallynon-toxic in the amounts employed. In addition, the substance may beincorporated into sustained-release preparations and devices.

The cobalamin conjugates can also be administered intravenously orintraperitoneally by infusion or injection. Solutions of the substancecan be prepared in water, optionally mixed with a nontoxic surfactant.Dispersions can also be prepared in glycerol, liquid polyethyleneglycols, triacetin, and mixtures thereof and in oils. Under ordinaryconditions of storage and use, these preparations contain a preservativeto prevent the growth of microorganisms.

The pharmaceutical dosage forms suitable for injection or infusion caninclude sterile aqueous solutions or dispersions or sterile powderscomprising the substance which are adapted for the extemporaneouspreparation of sterile injectable or infusible solutions or dispersions,optionally encapsulated in liposomes. In all cases, the ultimate dosageform must be sterile, fluid and stable under the conditions ofmanufacture and storage. The liquid carrier or vehicle can be a solventor liquid dispersion medium comprising, for example, water, normalsaline, ethanol, a polyol (for example, glycerol, propylene glycol,liquid polyethylene glycols, and the like), vegetable oils, nontoxicglyceryl esters, and suitable mixtures thereof. The proper fluidity canbe maintained, for example, by the formation of liposomes, by themaintenance of the required particle size in the case of dispersions orby the use of surfactants. The prevention of the action ofmicroorganisms can be brought about by various antibacterial andantifungal agents, for example, parabens, chlorobutanol, phenol, sorbicacid, thimerosal, and the like. In many cases, it will be preferable toinclude isotonic agents, for example, sugars, buffers or sodiumchloride. Prolonged absorption of the injectable compositions can bebrought about by the use in the compositions of agents delayingabsorption, for example, aluminum monostearate and gelatin.

Sterile injectable solutions are prepared by incorporating the substancein the required amount in the appropriate solvent with various of theother ingredients enumerated above, as required, followed by filtersterilization. In the case of sterile powders for the preparation ofsterile injectable solutions, the preferred methods of preparation arevacuum drying and the freeze drying techniques, which yield a powder ofthe active ingredient plus any additional desired ingredient present inthe previously sterile-filtered solutions.

Useful dosages of the compounds of formula I can be determined bycomparing their in vitro activity, and in vivo activity in animalmodels. Methods for the extrapolation of effective dosages in mice, andother animals, to humans are known to the art; for example, see U.S.Pat. No. 4,938,949.

The amount of the substance required for use in treatment will vary notonly with the particular salt selected but also with the route ofadministration, the nature of the condition being treated and the ageand condition of the patient and will be ultimately at the discretion ofthe attendant physician or clinician.

In general, however, a suitable dose will be in the range of from about0.5 to about 100 mg/kg, e.g., from about 10 to about 75 mg/kg of bodyweight per day, such as 3 to about 50 mg per kilogram body weight of therecipient per day, preferably in the range of 6 to 90 mg/kg/day, mostpreferably in the range of 15 to 60 mg/kg/day.

The substance is conveniently administered in unit dosage form; forexample, containing 5 to 1000 mg, conveniently 10 to 750 mg, mostconveniently, 50 to 500 mg of active ingredient per unit dosage form.

Ideally, the substance should be administered to achieve peak plasmaconcentrations of from about 0.5 to about 75 μM, preferably, about 1 to50 μM, most preferably, about 2 to about 30 μM. This may be achieved,for example, by the intravenous injection of a 0.05 to 5% solution ofthe substance, optionally in saline, or orally administered as a boluscontaining about 1-100 mg of the substance. Desirable blood levels maybe maintained by continuous infusion to provide about 0.01-5.0 mg/kg/hror by intermittent infusions containing about 0.4-15 mg/kg of thesubstance.

The substance may conveniently be presented in a single dose or asdivided doses administered at appropriate intervals, for example, astwo, three, four or more sub-doses per day.

The invention will now be illustrated by the following non-limitingExamples.

EXAMPLES Example 1

Proposed Synthesis of Daunorubicin- and Doxorubicin-Cobalamin Conjugates

Modification of the carbohydrate moiety (daunosamine) of daunorubicin(1) with L-leucine can be accomplished by reacting daunorubicin HCl (0.5g) in 100 mL borate buffer pH=10 (containing KCl) withL-leucine-carboxyanhydride (1 mmol in 5 mL acetone) at 0° C. undernitrogen. After reaction for 5 minutes at 0° C., the mixture can beacidified to pH 3.5 with H₂SO₄, stirred for 15 minutes and adjusted topH=7 to give the desired L-leucyl daunorubicin (2). Reaction of (2) witha cobalamin-mono or dicarboxylic acid in the presence of a water-solublecarbodiimide and hydroxybenzotriazole will yield thedaunorubicin-cobalamin conjugates (3). These conjugates can be isolatedvia the usual phenol extraction, extensive washing of the phenol phasewith water and finally displacing the cobalamin-conjugates from thephenol phase into water by the addition of acetone and diethyl ether.

Modification of doxorubicin should be similar (Ger. Patent 1,813,518,Jul. 10, 1969; Chem Abstracts, 71, 91866 (1969)). D.Deprez-Decampaneere, M. Mosquelier, R. Bourain and A. Trosect, Curr.Chemother. Proc., Int. Congr. Chemother., 10th, p. 1242 (1978) havefound that N-(L-leucyl) daunorubicin but not the D isomer was hydrolyzedin vivo to regenerate daunorubicin. See, “Doxorubicin, AnticancerAntibiotics,” Federico Arcamone, Medicinal Chemistry, Vol. 17, AcademicPress, 1981.

All publications, patents, and patent documents are incorporated byreference herein, as though individually incorporated by reference. Theinvention has been described with reference to various specific andpreferred embodiments and techniques. However, it should be understoodthat many variations and modifications may be made while remainingwithin the spirit and scope of the invention.

1. A compound wherein a residue of a compound of formula I (FIG. 1) islinked directly or by a linker to a residue of one or morechemotherapeutic agents; wherein X is CN, OH, CH₃, or adenosyl; or apharmaceutically acceptable salt thereof.
 2. The compound of claim 1wherein a residue of a chemotherapeutic agent is directly linked to aresidue of the b, d or e-carboxamide of the compound of formula I. 3.The compound of claim 1 wherein a residue of a chemotherapeutic agent islinked by a linker to a residue of the b-, d- or e-carboxamide of thecompound of formula I.
 4. The compound of claim 1 wherein a residue of achemotherapeutic agent is directly linked to the b-carboxamide of thecompound of formula I.
 5. The compound of claim 1 wherein a residue of achemotherapeutic agent is linked by a linker to a residue of theb-carboxamide of the compound of formula I.
 6. The compound of claim 1wherein a residue of a chemotherapeutic agent is directly linked to aresidue of the d-carboxamide of the compound of formula I.
 7. Thecompound of claim 1 wherein a residue of a chemotherapeutic agent islinked by a linker to a residue of the d-carboxamide of the compound offormula I.
 8. The compound of claim 1 wherein a residue of achemotherapeutic agent is directly linked to a residue of thee-carboxamide of the compound of formula I.
 9. The compound of claim 1wherein a residue of a chemotherapeutic agent is linked by a linker to aresidue of the e-carboxamide of the compound of formula I.
 10. Thecompound of claim 1 wherein a residue of a first chemotherapeutic agentis linked directly or by a linker to a residue of the b-carboxamide ofthe compound of formula I and a residue of a second chemotherapeuticagent is linked directly or by a linker to a residue of thed-carboxamide of the compound of formula I.
 11. The compound of claim 1wherein a residue of a first chemotherapeutic agent is linked by alinker to a residue of the b-carboxamide of the compound of formula Iand a residue of a second chemotherapeutic agent is linked by a linkerto a residue of the d-carboxamide of the compound of formula I.
 12. Thecompound of claim 1 wherein the chemotherapeutic agent is anantineoplastic agent.
 13. The compound of claim 12 wherein theantineoplastic agent is a cytotoxic agent.
 14. The compound of claim 13wherein the cytotoxic agent is doxorubicin or paclitaxel.
 15. Thecompound of any one of claims 1, 3, 5, 7, 9, 10, and 11 wherein at leastone linker is of the formula W-A-Q wherein A is (C₁-C₆)alkyl,(C₂-C₆)alkenyl, (C₂-C₆)alkynyl, (C₃-C₈)cycloalkyl, or (C₆-C₁₀)aryl,wherein W and Q are each independently —N(R)C(═O)—, —C(═O)N(R)—,—OC(═O)—, —C(═O)O—, —O—, —S—, —S(O)—, —S(O)₂—, —N(R)—, —C(═O)—, or adirect bond; wherein each R is independently H or (C₁-C₆)alkyl.
 16. Thecompound of claim 15 wherein W and Q are each —N(R)—.
 17. The compoundof any one of claims 1, 3, 5, 7, 9, 10, and 11 wherein at least onelinker is of the formula W—(CH₂)_(n)-Q wherein, n is between about 1 andabout 20, between about 1 and about 15, between about 2 and about 10,between about 2 and about 6, or between about 4 and about 6; wherein Wand Q are each independently —N(R)C(═O)—, —C(═O)N(R)—, —OC(═O)—,—C(═O)O—, —O—, —S—, —S(O)—, —S(O)₂—, —C(═O)—, —N(R)—, or a direct bond;wherein each R is independently H or (C₁-C₆)alkyl.
 18. The compound ofclaim 17 wherein at least one of W and Q is —N(R)—.
 19. The compound ofclaim 18 wherein n is in the range from about 2 to about 6, inclusive.20. The compound of any one of claims 1, 3, 5, 7, 9, 10, and 11 whereinthe linker is a divalent radical formed from a peptide or an amino acid.21. The compound of claim 20 wherein the peptide comprises 2 to about 25amino acids.
 22. The compound of claim 20 wherein the peptide ispoly-L-lysine, containing about 8 to about 11 residues.
 23. The compoundof any one of claims 1, 3, 5, 7, 9, 10, and 11 wherein the linker is a1,ω-divalent radical formed from a peptide.
 24. The compound of any oneof claims 1, 3, 5, 7, 9, 10, and 11 wherein the linker separates theresidue of a compound of formula I from the residue of thechemotherapeutic agent by about 5 angstroms to about 50 angstroms.
 25. Acompound wherein a residue of a compound of formula I is linked directlyor by a linker to a residue of a chemotherapeutic agent through the6-position and wherein a residue of the compound of formula I is linkeddirectly or by a linker to a residue of one or more additionalchemotherapeutic agents; or a pharmaceutically acceptable salt thereof.26. The compound of claim 25 wherein a residue of a chemotherapeuticagent is directly linked to a residue of the b-, d- or e-carboxamide ofthe compound of formula I.
 27. The compound of claim 25 wherein aresidue of a chemotherapeutic agent is linked by a linker to a residueof the b-, d- or e-carboxamide of the compound of formula I.
 28. Thecompound of claim 25 wherein a residue of a chemotherapeutic agent isdirectly linked to the b-carboxamide of the compound of formula I. 29.The compound of claim 25 wherein a residue of a chemotherapeutic agentis linked by a linker to a residue of the b-carboxamide of the compoundof formula I.
 30. The compound of claim 25 wherein a residue of achemotherapeutic agent is directly linked to a residue of thed-carboxamide of the compound of formula I.
 31. The compound of claim 25wherein a residue of a chemotherapeutic agent is linked by a linker to aresidue of the d-carboxamide of the compound of formula I.
 32. Thecompound of claim 25 wherein a residue of a chemotherapeutic agent isdirectly linked to a residue of the e-carboxamide of the compound offormula I.
 33. The compound of claim 25 wherein a residue of achemotherapeutic agent is linked by a linker to a residue of thee-carboxamide of the compound of formula I.
 34. The compound of claim 25wherein a residue of a chemotherapeutic agent is linked directly or by alinker to a residue of the b-carboxamide of the compound of formula Iand a residue of a second chemotherapeutic agent is linked directly orby a linker to a residue of the d-carboxamide of the compound of formulaI.
 35. The compound of claim 25 wherein a residue of a chemotherapeuticagent is linked by a linker to a residue of the b-carboxamide of thecompound of formula I and a residue of a second chemotherapeutic agentis linked by a linker to a residue of the d-carboxamide of the compoundof formula I.
 36. The compound of any one of claims 25, 27, 29, 31, 33,34 and 35 wherein at least one linker is of the formula W-A-Q wherein Ais (C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, (C₃-C₈)cycloalkyl, or(C₆-C₁₀)aryl, wherein W and Q are each independently —N(R)C(═O)—,—C(═O)N(R)—, —OC(═O)—, —C(═O)O—, —O—, —S—, —S(O)—, —S(O)₂—, —N(R)—,—C(═O)—, or a direct bond; wherein each R is independently H or(C₁-C₆)alkyl.
 37. The compound of claim 36 wherein at least one of W andQ is —N(R)—.
 38. The compound of any one of claims 25, 27, 29, 31, 33,34 and 35 wherein at least one linker is of the formula W—(CH₂)_(n)-Qwherein, n is between about 1 and about 20, between about 1 and about15, between about 2 and about 10, between about 2 and about 6, orbetween about 4 and about 6; wherein W and Q are each independently—N(R)C(═O)—, —C(═O)N(R)—, —OC(═O)—, —C(═O)O—, —O—, —S—, —S(O)—, —S(O)₂—,—C(═O)—, —N(R)—, or a direct bond; wherein each R is independently H or(C₁-C₆)alkyl.
 39. The compound of claim 38 wherein at least one of W andQ is —N(R)—.
 40. The compound of claim 38 wherein n is in the range ofabout 2 to about 6, inclusive.
 41. The compound of anyone of claims 25,27, 29, 31, 33, 34 and 35 wherein a linker is a divalent radical formedfrom a peptide or an amino acid.
 42. The compound of claim 41 whereinthe peptide comprises 2 to about 25 amino acids.
 43. The compound ofclaim 42 wherein the peptide is poly-L-lysine, containing about 8 toabout 11 residues.
 44. The compound of any one of claims 25, 27, 29, 31,33, 34 and 35 wherein the linker is a 1,ω-divalent radical formed from apeptide.
 45. The compound of any one of claims 25, 27, 29, 31, 33, 34and 35 wherein the linker separates the residue of a compound of formulaI from the residue of the chemotherapeutic agent by about 5 angstroms toabout 50 angstroms.
 46. The compound of claim 25 wherein thechemotherapeutic agent is an antineoplastic agent.
 47. The compound ofclaim 46 wherein the antineoplastic agent is a cytotoxic agent.
 48. Thecompound of claim 47 wherein the cytotoxic agent is doxorubicin orpaclitaxel.
 49. A compound of formula II

wherein

is a residue of the compound of formula I; X is CN, OH, CH₃, adenosyl,or LL-TT wherein LL is a linker or is absent and TT is a residue of achemotherapeutic agent; L is a linker or absent; and T is a residue of achemotherapeutic agent; or a pharmaceutically acceptable salt thereof.50. The compound of claim 49 wherein L and LL are each independently ofthe formula W-A-Q wherein A is (C₁-C₆)alkyl, (C₂-C₆)alkenyl,(C₂-C₆)alkynyl, (C₃-C₈)cycloalkyl, or (C₆-C₁₀)aryl, wherein W and Q areeach independently —N(R)C(═O)—, —C(═O)N(R)—, —OC(═O)—, —C(═O)O—, —O—,—S—, —S(O)—, —S(O)₂—, —N(R)—, —C(═O)—, or a direct bond; wherein each Ris independently H or (C₁-C₆)alkyl.
 51. The compound of claim 50 whereinat least one of W and Q is —N(R)—.
 52. The compound of claim 49 whereinL and LL are each independently of the formula W—(CH₂)_(n)-Q wherein, nis between about 1 and about 20, between about 1 and about 15, betweenabout 2 and about 10, between about 2 and about 6, or between about 4and about 6; wherein W and Q are each independently —N(R)C(═O)—,—C(═O)N(R)—, —OC(═O)—, —C(═O)O—, —O—, —S—, —S(O)—, —S(O)₂—, —C(═O)—,—N(R)—, or a direct bond; wherein each R is independently H or(C₁-C₆)alkyl.
 53. The compound of claim 52 wherein at least one of W andQ is —N(R)—.
 54. The compound of claim 52 wherein n is between about 2and about
 6. 55. The compound of claim 49 wherein L separates T and theresidue by about 5 angstroms to about 200 angstroms.
 56. The compound ofclaim 49 wherein at least one of L and LL is a divalent radical formedfrom a peptide or an amino acid.
 57. The compound of claim 56 whereinthe peptide comprises 2 to about 25 amino acids.
 58. The compound ofclaim 56 wherein the peptide is poly-L-lysine, containing about 8 toabout 11 residues.
 59. The compound of claim 49 wherein at least one ofL and LL is a 1,ω-divalent radical formed from a peptide or an aminoacid.
 60. The compound of claim 49 wherein at least one of T and TT is aresidue of paclitaxel or doxorubicin, or a pharmaceutically acceptablesalt thereof.
 61. The compound of claim 49 wherein the (C═O) in thegroup is attached to L-T at the b-, d- or e-position.
 62. A compound offormula II

wherein

is a residue of the compound of formula I; X is LL-TT wherein LL is alinker or is absent and TT is a residue of a chemotherapeutic agent; Lis a linker or absent; and T is a residue of a chemotherapeutic agent;or a pharmaceutically acceptable salt thereof.
 63. The compound of claim62 wherein L and LL are each independently of the formula W-A-Q whereinA is (C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, (C₃-C₈)cycloalkyl, or(C₆-C₁₀)aryl, wherein W and Q are each independently —N(R)C(═O)—,—C(═O)N(R)—, —OC(═O)—, —C(═O)O—, —O—, —S—, —S(O)—, —S(O)₂—, —N(R)—,—C(═O)—, or a direct bond; wherein each R is independently H or(C₁-C₆)alkyl.
 64. The compound of claim 63 wherein at least one of W andQ is —N(R)—.
 65. The compound of claim 62 wherein L and LL are eachindependently of the formula W—(CH₂)_(n)-Q wherein, n is between about 1and about 20, between about 1 and about 15, between about 2 and about10, between about 2 and about 6, or between about 4 and about 6; whereinW and Q are each independently —N(R)C(═O)—, —C(═O)N(R)—, —OC(═O)—,—C(═O)O—, —O—, —S—, —S(O)—, —S(O)₂—, —C(═O)—, —N(R)—, or a direct bond;wherein each R is independently H or (C₁-C₆)alkyl.
 66. The compound ofclaim 65 wherein at least one of W and Q is —N(R)—.
 67. The compound ofclaim 65 wherein n is between about 2 and about
 6. 68. The compound ofclaim 62 wherein L separates T and the residue by about 5 angstroms toabout 200 angstroms.
 69. The compound of claim 62 wherein at least oneof L and LL is a divalent radical formed from a peptide or an aminoacid.
 70. The compound of claim 69 wherein the peptide comprises 2 toabout 25 amino acids.
 71. The compound of claim 69 wherein the peptideis poly-L-lysine, containing about 8 to about 11 residues.
 72. Thecompound of claim 62 wherein at least one of L and LL is a 1,ω-divalentradical formed from a peptide.
 73. The compound of claim 62 wherein atleast one of T and TT is a residue of paclitaxel or doxorubicin, or apharmaceutically acceptable salt thereof.
 74. The compound of claim 62wherein (C═O) in the group is attached to L-T is attached at the b-, d-or e-position.
 75. A compound of formula III:

wherein

X is CN, OH, CH₃, adenosyl, or ZZ-TT wherein ZZ is a linker or is absentand TT is a residue of a chemotherapeutic agent; Z is —N(R)—, —O—, or—S—, wherein R is H or (C₁-C₆)alkyl or absent; and T is a residue of achemotherapeutic agent; or a pharmaceutically acceptable salt thereof.76. The compound of claim 75 wherein Z and ZZ are each independently ofthe formula W-A-Q wherein A is (C₁-C₆)alkyl, (C₂-C₆)alkenyl,(C₂-C₆)alkynyl, (C₃-C₈)cycloalkyl, or (C₆-C₁₀)aryl, wherein W and Q areeach independently —N(R)C(═O)—, —C(═O)N(R)—, —OC(═O)—, —C(═O)O—, —O—,—S—, —S(O)—, —S(O)₂—, —N(R)—, —C(═O)—, or a direct bond; wherein each Ris independently H or (C₁-C₆)alkyl.
 77. The compound of claim 76 whereinat least one of W and Q is —N(R)—.
 78. The compound of claim 75 whereinZ and ZZ are each independently of the formula W—(CH₂)_(n)-Q wherein, nis between about 1 and about 20, between about 1 and about 15, betweenabout 2 and about 10, between about 2 and about 6, or between about 4and about 6; wherein W and Q are each independently —N(R)C(═O)—,—C(═O)N(R)—, —OC(═O)—, —C(═O)O—, —O—, —S—, —S(O)—, —S(O)₂—, —C(═O)—,—N(R)—, or a direct bond; wherein each R is independently H or(C₁-C₆)alkyl.
 79. The compound of claim 78 wherein at least one of W andQ is —N(R)—.
 80. The compound of claim 78 wherein n is between about 2and about
 6. 81. The compound of claim 75 wherein Z separates T and theresidue by about 5 angstroms to about 200 angstroms.
 82. The compound ofclaim 75 wherein at least one of Z and ZZ is a divalent radical formedfrom a peptide or an amino acid.
 83. The compound of claim 82 whereinthe peptide comprises 2 to about 25 amino acids.
 84. The compound ofclaim 75 wherein the peptide is poly-L-lysine, containing about 8 toabout 11 residues.
 85. The compound of claim 75 wherein at least one ofZ and ZZ is a 1,ω-divalent radical formed from a peptide.
 86. Thecompound of claim 75 wherein the (C═O) in the group is attached to Z-Tat the b-, d- or e-position.
 87. The compound of claim 75 wherein atleast one of T and TT is a residue of an antineoplastic agent.
 88. Thecompound of claim 87 wherein the antineoplastic agent is a cytotoxicagent.
 89. The compound of claim 88 wherein the cytotoxic agent isdoxorubicin or paclitaxel.
 90. A compound of formula III:

wherein

is a residue of the compound of formula I; X is LL-TT wherein LL is alinker or is absent and TT is a residue of a chemotherapeutic agent; Zis —N(R)—, —O—, or —S—, wherein R is H, (C₁-C₆)alkyl, or absent; and Tis a residue of a chemotherapeutic agent; or a pharmaceuticallyacceptable salt thereof.
 91. The compound of claim 90 wherein Z and ZZare each independently of the formula W-A-Q wherein A is (C₁-C₆)alkyl,(C₂-C₆)alkenyl, (C₂-C₆)alkynyl, (C₃-C₈)cycloalkyl, or (C₆-C₁₀)aryl,wherein W and Q are each independently —N(R)C(═O)—, —C(═O)N(R)—,—OC(═O)—, —C(═O)O—, —O—, —S—, —S(O)—, —S(O)₂—, —N(R)—, —C(═O)—, or adirect bond; wherein each R is independently H or (C₁-C₆)alkyl.
 92. Thecompound of claim 91 wherein at least one of W and Q is —N(R)—.
 93. Thecompound of claim 90 wherein Z and ZZ are each independently of theformula W—(CH₂)_(n)-Q wherein, n is between about 1 and about 20,between about 1 and about 15, between about 2 and about 10, betweenabout 2 and about 6, or between about 4 and about 6; wherein W and Q areeach independently —N(R)C(═O)—, —C(═O)N(R)—, —OC(═O)—, —C(═O)O—, —O—,—S—, —S(O)—, —S(O)₂—, —C(═O)—, —N(R)—, or a direct bond; wherein each Ris independently H or (C₁-C₆)alkyl.
 94. The compound of claim 93 whereinat least one of W and Q is —N(R)— wherein each R is independently H or(C₁-C₆)alkyl.
 95. The compound of claim 93 wherein n is between about 2and about
 6. 96. The compound of claim 90 wherein Z separates T and theresidue by about 5 angstroms to about 200 angstroms.
 97. The compound ofclaim 90 wherein at least one of Z and ZZ is a divalent radical formedfrom a peptide or an amino acid.
 98. The compound of claim 97 whereinthe peptide comprises 2 to about 25 amino acids.
 99. The compound ofclaim 90 wherein the peptide is poly-L-lysine, containing about 8 toabout 11 residues.
 100. The compound of claim 90 wherein at least one ofZ and ZZ is a 1,ω-divalent radical formed from a peptide.
 101. Thecompound of claim 90 wherein (C═O) in the group is attached to Z-T atthe b-, d- or e-position.
 102. The compound of claim 90 wherein at leastone of T and TT is a residue of an antineoplastic agent.
 103. Thecompound of claim 102 wherein the antineoplastic agent is a cytotoxicagent.
 104. The compound of claim 103 wherein the cytotoxic agent isdoxorubicin or paclitaxel.
 105. A compound wherein a residue of acompound of formula I (FIG. 1) is linked directly or by a linker to aresidue of one or more chemotherapeutic agents; wherein X is CN, OH,CH₃, or adenosyl; wherein the compound of formula I is also linkeddirectly or by a linker to a detectable radionuclide; or apharmaceutically acceptable salt thereof.
 106. The compound of claim 105wherein the detectable radionuclide is linked to a residue of the b, dor e-carboxamide of the compound of formula I.
 107. The compound ofclaim 105 wherein the detectable radionuclide is linked by a linker to aresidue of the compound of formula I.
 108. The compound of claim 105wherein the detectable radionuclide is directly linked to a residue ofthe compound of formula I.
 109. The compound of claim 105 wherein thedetectable radionuclide is a non-metallic radionuclide.
 110. Thecompound of claim 109 wherein the non-metallic radionuclide isCarbon-11, Fluorine-18, Bromine-76, Iodine-123, or Iodine-124.
 111. Apharmaceutical composition comprising a compound of any one of claims1-110 and a pharmaceutically acceptable carrier.
 112. A compound of anyone of claims 1-110 for use in medical therapy or diagnosis.
 113. Theuse of claim 105 for the manufacture of a medicament for imaging a tumorin a mammal.
 114. The use of claim 113 wherein the tumor is located inthe breast, lung, thyroid, lymph node, kidney, ureter, bladder, ovary,teste, prostate, bone, skeletal muscle, bone marrow, stomach, esophagus,small bowel, colon, rectum, pancreas, liver, smooth muscle, brain,spinal cord, nerves, ear, eye, nasopharynx, oropharynx, salivary glands,or the heart.
 115. The use of a compound of any one of claims 1-110 forthe manufacture of a medicament for treating a tumor in a mammal. 116.The use of claim 115 wherein the tumor is located in the breast, lung,thyroid, lymph node, kidney, ureter, bladder, ovary, teste, prostate,bone, skeletal muscle, bone marrow, stomach, esophagus, small bowel,colon, rectum, pancreas, liver, smooth muscle, brain, spinal cord,nerves, ear, eye, nasopharynx, oropharynx, salivary glands, or theheart.
 117. A method of treating a tumor in a mammal in need of suchtreatment comprising administering to the mammal an effective amount ofa compound of any one of claims 1-110.
 118. The method of claim 117wherein the tumor is located in the breast, lung, thyroid, lymph node,kidney, ureter, bladder, ovary, teste, prostate, bone, skeletal muscle,bone marrow, stomach, esophagus, small bowel, colon, rectum, pancreas,liver, smooth muscle, brain, spinal cord, nerves, ear, eye, nasopharynx,oropharynx, salivary glands, or the heart.
 119. A method of imaging atumor in a mammal in need of such imaging comprising administering tothe mammal an effective amount of a compound of claim 105; and detectingthe presence of the compound.
 120. The method of claim 119 wherein thetumor is located in the breast, lung, thyroid, lymph node, kidney,ureter, bladder, ovary, teste, prostate, bone, skeletal muscle, bonemarrow, stomach, esophagus, small bowel, colon, rectum, pancreas, liver,smooth muscle, brain, spinal cord, nerves, ear, eye, nasopharynx,oropharynx, salivary glands, or the heart.